**1. Introduction**

The human gastrointestinal (GI) tract is colonized by a rich microbial community consisting of more than 10<sup>14</sup> microorganisms, defining microbiota, and more than 5,000,000 genes defining microbiome [1,2]. The microbiota is composed of bacteria, viruses and yeasts [3]. In healthy conditions, these microorganisms colonize mucosal surfaces, particularly the large intestine, and talk closely with them; in this way they regulate important physiological functions [4,5]. First, they are involved in metabolism of nutrients and drugs and vitamin production [6]. Then, through food fermentation, bacteria produce some short-chain fatty acids (SCFAs), for example butyrate, which have trophic effects on the GI epithelium [7]. Furthermore, gu<sup>t</sup> microbiota influences the immune system through its antigenic e ffects. The interaction between gu<sup>t</sup> microbiota, intestinal epithelial cells and the mucosal immune system creates an environment that prevents overgrowth of the host pathogenic microorganisms [8] and limits the colonization of the intestinal tract by foreign pathogens [9–11].

In healthy people gu<sup>t</sup> microbiota is characterized by richness in microorganisms and high diversity of species. This situation is called *eubiosis*. In this microenvironment, bacteria are predominant and represent the main group of microorganisms that are strictly anaerobics and extremophiles. *Firmicutes* and *Bacteroidetes* represent the main bacterial phyla, up to 85–90% of total microorganisms, while *Actinobacteria* and *Proteobacteria* are less plentiful, representing up to 10% [12].

In this condition, commensal bacterial species are predominant compared to pathological ones.

Conversely, when this ecosystem balance is perturbed (i.e., by use of antibiotics, motility disorders, diet, host genetic features, etc.) [3], there is a condition called *dysbiosis,* characterized by a lowering in diversity of bacterial species, with abundance of pathogenic ones, and a loss of microbiome physiological functions [13,14]. In some cases, in this dysbiotic environment, there is a reduction of tight junctions between enterocytes, leading to a compromised function of mucosal barrier integrity; this alteration, named leaky gut, sometimes allows bacterial translocation and plays a key role in the development of GI and systemic diseases [11,15].

The composition of gu<sup>t</sup> microbiota may be strongly influenced by both pathological conditions and environmental factors, such as age, diet, drugs, stress [16]. Besides, the abundance and the variety of di fferent species within an individual microbial system (i.e., a single sample) is called α-diversity, while β-diversity refers to di fferences between microbial communities from di fferent environments (i.e., di fferent samples or di fferent individuals) [17].

In clinical practice, we may manipulate microbiota by administering prebiotics, probiotics or synbiotics, through fecal microbiota transplantation (FMT). Prebiotics are defined as "a substrate that is selectively utilized by host microorganisms conferring a health benefit" [18]; the main prebiotics that have healthy benefits are non-digestible fructooligosaccharides (FOS) and galactans (GOS), preferentially metabolized by *Bifidobacterium*spp. Other examples of prebiotics are polyunsaturated fatty acids (PUFAs) and inulin [19]. Intestinal microorganisms can readily utilize prebiotics, transforming them in metabolic products, such as SCFAs, i.e., propionate, butyrate, acetate. These products are crucial for correct intestinal health. Prebiotics are now largely used in clinical practice for treating many diseases, such as inflammatory bowel disease (IBD) [20], irritable bowel syndrome (IBS) [21], metabolic syndrome [22]. Conversely, probiotics are defined as "live microorganisms that confer a health benefit on the host" [23]. Probiotic foods contain safe live microbes with su fficient evidence for a general beneficial e ffect in mammals [24]. Synbiotics are a mixed product with a combination of probiotics and prebiotics. Finally, FMT consists of "the infusion of faecal samples from a healthy donor to the GI tract of a recipient patient, in order to cure a specific disease, improving alteration of gu<sup>t</sup> microbiota" [25]. To date, the only indication to perform FMT is the recurrent and refractory (non-responder to conventional antibiotics, i.e., vancomycin, fidaxomicin or metronidazole) *Clostridium di*ffi*cile* infection with an e fficiency rate standing at more than 80–85% [25].

Due to these novelties, microbiota is now a worldwide field of interest and investigations are growing in the recent years. Several studies analyzed the involvement of intestinal dysbiosis in the development of intestinal and extra-intestinal diseases, such as IBD [26], celiac disease [27], IBS [28], multiple sclerosis [29], rheumatologic diseases [30], Alzheimer's disease [31], colorectal and gastric cancer [32]. On the contrary, data about correlation between microbiota and pancreatic diseases are still scarce and controversial.

Few studies described the presence of bacteria in pancreatic tissue; they found bacteria in pancreatic ducts of subjects with chronic pancreatitis or in pancreatic tissue of pancreatic cancer patients. Instead, recently, some authors analyzed microbiome in pancreatic samples and duodenal tissues from patients underwent pancreatectomy, finding a similar bacterial DNA profiles; this may sugges<sup>t</sup> a bacterial translocation from the gu<sup>t</sup> into the pancreas [33]. Due to the impossibility to collect pancreatic tissues routinely, a lot of studies analyzed gu<sup>t</sup> microbiome from fecal samples.

In this review, we analyze the actual available data in literature about microbiota and pancreas in health and disease.
